A user group of seven NIH funded investigators requests $591,278.10 to purchase a Nikon High Content Screening (HCS) Microscope together with a PerkinElmer Columbus Image Data Storage and Analysis System, which will be housed in the Department of MCB/College of Biological Sciences Imaging Facility at the University of California, Davis. The need for a high throughput HCS system is a natural outgrowth of the high quality images routinely obtained in this facility and will allow researchers to develop and mine screens based on their high- resolution structural/spatial information. The selected HCS system is a sensible and cost- effective compromise between the moderately-priced scanners in a box, which allow high throughput acquisition at insufficient resolution for many model organisms, and the high-end scanners, which provide the necessary image resolution, but are very expensive to purchase and maintain. The requested HCS microscope and analysis system is very appropriate for our academic facility environment because it is easy to upgrade, provides powerful image management and analysis software with accessible user interfaces, and is very flexible, which is in contrast to the box systems, which are better suited for the drug industry. As detailed in the proposal, the availability of water or oil immersion lenses of high numerical aperture is key to productive use of an HCS system as many of our users employ small-sized organisms, such as budding yeast or Giardia, and require high spatial resolution for HCS. We show that we can obtain such structural detail with a commercial high-end scanner equipped with the requested Columbus storage and analysis software. However, we judge the operating and maintenance costs of such an instrument to be prohibitive. As we show with preliminary data, the alternative instrument proposed allows us to obtain high content data and image analysis, while comfortably operating within the fiscal restraints of our shared Imaging Facility. Management of the proposed instrument will be integrated into the existing, successful Imaging Facility, which is coordinated by a full time, PhD-level scientist and guided by a faculty-based imaging committee. The MCB/CBS Imaging Facility currently serves a large number of UC-Davis researchers: since July 2005, 364 scientists from 135 laboratories in 37 departments have paid for more than 30,919 hours of instrument time generating more than $1,038,684 of income to help operate the Facility. As detailed by the research of our seven major PIs, many of these existing users will find the proposed screening microscope useful.